1. Field of the Invention
This invention relates to novel compositions of PGE-type prostaglandins; a method for stabilizing PGE-type compounds in solution; and to a process for dispensing PGE-type prostaglandins for oral adminstration.
2. Related Disclosures
Prostaglandins have classically been described as chemically related 20 carbon chain hydroxy fatty acids having the basic skeleton of prostanoic acid: ##STR1## this structure is the basis for prostaglandin numbering and nomenclature.
Naturally occuring prostaglandins are derivatives of prostanoic acid. For descriptive purposes, four types are recognized. The type distinction is based primarily on pentane ring subtituents and structural orientation. Although they can be named as derivatives of prostanoic acid, they are conventionally referred to by the letters A, B, E and F. Prostaglandins having an hydroxyl group at the C-11 position and a keto group at the C-9 position are known as PGE or PGE-type compounds. Those having hydroxyl groups at C-9 and C-11 are known as the PGF series and are further designated by an .alpha. or .beta. suffix to indicate the configuration of the hydroxyl group at said position. Series A and B have a keto group at C-9 and a double bond between C-10 and C-11 or C-8 and C-12 respectively. The natural compounds are the .alpha.-hydroxy substituted compounds. Prostaglandins may contain different series of unsaturation in the molecule, particularly at C-5, C-13 and C-17. The unsaturation is also indicated by a suffix. Thus, for example, PGF.sub.1 and PGE.sub.1 series refer to prostanoic acids having a trans-olefin bond at the C-13 position, while the PGF.sub.2 and PGE.sub.2 series refer to prostadienoic acids having a cis-olefin bond at the C-5 position and a trans-olefin bond at the C-13 position. For a review on prostaglandins and the definition of primary prostaglandins, see for example, S. Bergstrom, Recent Progress in Hormone Research 22, pp. 153-175 (1966) and Science 157, p. 382 (1967) by the same author.
Prostagladins generally act to stimulate gastrointestional and reproductive smooth muscles, affect relaxation and contraction of respiratory smooth muscle, are hypotensives, and inhibit lipolysis of fatty acids, gastric acid secretion and blood platelet aggregation. There is not a precise structure-activity relationship in the prostaglandin family as much cross-activity is evident.
A great number of studies have been undertaken to enhance, extend and otherwise modify the activity of naturally occurring prostanoic acids. The majority of these studies have focused on modification of two areas, the two side chains and substituents attached to the cyclopropane moiety [see, for example, U. Axen et al, Synthesis Vol. 1, John Whilely and Sons Inc., New York, N.Y. 1973 and P. H. Bently, Chem. Soc. Reviews, 2, 29 (1973)].
Of special interest to this invention is that group of prostaglandins which are labile in most standard pharmaceutical compositions, particularly PGE compounds and PGE-type compounds. In many instances the cyclopentane ring substituents substantially affect the prostaglandin's level of activity. Compounds which loose an oxygen from either C-9 or C-11 on the cyclopentane ring or which have these positions altered show altered levels of activity. For instance PGE.sub.2 .alpha., which has a carbonyl group at C-9 and an hydroxyl group at C-11 stimulates smooth muscle tissue but loss of the C-11 hydroxyl group to give a double bond in the cyclopentane ring, the PGA or PGB forms, show little or no such activity. This conversion is chemically facile because of the presence of the carbonyl group at C-9 in the PGE and PGE-type compounds which makes the hydroxyl group at C-11 labile to either base or acid dehydroxylation. The product of this dehydroxylation is a double bond conjugated with the carbonyl group of C-9, a stable chemical entity. Under acid conditions PGE-type compounds convert readily to the PGA form. Basic conditions cause PGE-type compounds to dehydroxylate and rearrange to the PGB form. In the case of PGE.sub.2 type compounds this latter form is particularly stable because the C-9 carbonyl is now conjugated with the C-8/C-12 and C-13/C-14 double bonds. Similar degradation patterns have been observed in most compounds which have PGE-type cyclopentane ring substituents.
Initial efforts at providing easily dispensible dose formulations of prostaglandins, particularly for PGE-type compounds, met with difficulty. Aqueous PGE solutions were found to undergo rapid loss of activity when stored at temperatures above 0.degree. C. at any pH, but particularly under alkaline conditions. Hydrous solutions adjusted to pH 5-7 were found to be most stable but loss of activity was still so rapid, drug concentrations after several months were very uncertain. Even in neutral or neat solutions there was found gradual degradation. Similar rapid degradation under these conditions have been observed in most compounds which have PGE-type cyclopentane ring substituents.
Various attempts have been made to formulate stable solutions of PGE-type compounds. Stabilization of these compounds has been observed in some solutions and in solid form at -20.degree. C. or lower. More practical and usable alternative methods for stabilizing these prostaglandins have been developed and are described, for example, in U.S. Pat. Nos. 3,749,800; 3,826,823; 3,829,579; 3,851,052; 3,833,725; and 4,221,793. These patents teach the use of such solvents as lower molecular weight alcohols, polyalkylene glycols, dialkylated polyalkylene glycols, triacetin, dimethylacetamide and triethylcitrate. All these disclosure contain the limitation that the solvent and the resulting drug solution must be anhydrous, i.e. contain less than 0.5% water, in order to achieve stable formulations. The dialkylated polyalkylene glycols are excepted from this particular limitation, but prefered formulations using these solvents contain less than 0.5% water.
It has now been found that prostaglandins in general and specifically PGE and PGE-type prostaglandin compounds can be prepared into stable pharmaceutical solution by dissolving them in carbonate diesters. It has also been discovered that the presence of water in such a solution will not significantly affect drug stability even when water is present in an amount up to the solubility limit of water in the chosen carbonate diester. Prostaglandins stablized by such solvents are particularly adaptable for oral administration of therapeutic doses of prostaglandins.